The field of the invention is related to cardiovascular disease including cardiovascular disease secondary to atheroschlerosis and compositions and methods for treating or preventing cardiovascular disease secondary to atherosclerosis. The compositions and methods may be utilized for digesting atheroschlerotic plaques.
Cardiovascular disease secondary to atherosclerosis is the leading cause of death in the United States, accounting for 60% of total mortality in 2002. (See Rosamond W, et al. Circulation 2007; 115(5):E69-E171.) Approximately 16 million people in the United States have clinically manifested coronary heart disease, approximately 8 million have peripheral arterial disease, and over 5 million are stroke survivors. (See id.)
Atherosclerotic plaques evolve through a continuum of histological changes. Inflammation starts when endothelial cells become, activated and secrete adhesion molecules, and the vascular smooth muscle cells (VSMC) secrete chemokines and chemoattractants. Together, these agents attract monocytes, lymphocytes, mast cells, and neutrophils into the arterial wall. (See Katsuda S. et al. Arteriosclerosis and Thrombosis 1992; 12(4):494-502). VSMC also secrete into the extracellular matrix proteoglycans, collagen, and elastic fibers. Upon entry, monocytes transform into macrophages, take up lipids as multiple small inclusions, and become foam cells. Extracellular proteoglycans bind lipids and progressively increase their lipid-binding capacity by extension of their disaccharide arms. Some factors promote the death of macrophages and VSMC. The necrotic debris provokes further inflammation. Increasing accumulation of extracellular lipids coalesces into pools and causes cell necrosis. Fibrotic tissue forms a fibrous cap over the lipid-rich necrotic core. (See id.). New vaso vasorum with thin walls invade the diseased intima from the media. These fragile vessels of endothelium, lacking pericytes for support, may leak, producing hemorrhage within the arterial wall. These intramural hemorrhages provoke increased fibrous tissue deposition. Calcium deposits in the wall occur throughout all these steps, initially as small aggregates, and later as large nodules. (See Insull W. American Journal of Medicine 2009; 122(1):S3-S14). It is also known that type I, III, IV, V, and VI collagen are the main collagens within atherosclerotic plaques but the distribution varies by stage and progression of the lesion. (See Katsuda S. et al. Arteriosclerosis and Thrombosis 1992; 12(4):494-502). Thus, it is apparent that formation of atherosclerotic plaques follows a complex continuum of events.
Percutaneous vascular interventions and plaque debulking technology to treat the manifestations of cardiovascular disease secondary to atherosclerosis do exist. Currently available percutaneous therapies for severe atherosclerosis include angioplasty with or without stenting, cryoplasty, laser atherectomy, or remote atherectomy. The later category includes the use of the Silverhawk™ or Rockhawk Atherectomy™ devices, the Rotablator™, the Pathway Jetstream™, and the Diamondback Orbital Atherectomy™ system. Each of these therapies enlarges the lumen of the artery, thereby treating the underlying stenotic lesion. However, each of these therapies induces some form of trauma to the vascular wall. Angioplasty and stenting restores lumen patency by forcing the plaque against the wall of the artery under high pressure balloon inflations, thereby inducing significant trauma to the vascular wall Cryoplasty reduces plaque burden by initiating apoptosis of the cells in the atherosclerotic plaque by freezing these cells to a temperature of −10° C. Laser atherectomy and mechanical remote atherectomy devices debulk the plaque but do so in association with high thermal temperatures. In fact, the Rotablator rotational atherectomy device was found to result in temperature increases of 2-4° C. with minimal decelerations, but increases of 11-14° C. with continuous ablation or rapid decelerations. Therefore, each of the current FDA approved therapies induces some form of mechanical injury to the vessel wall, which ultimately stimulates the development of neointimal hyperplasia and results in significant arterial restenosis. Furthermore, these therapies are costly, and require considerable time to debulk long segments of plaque. Therefore, new methodologies to reduce atherosclerotic plaques without inducing mechanical trauma to the arterial wall are desirable.
Here a new methodology for treating atherosclerotic lesions is proposed and developed through the optimization of a “digestion” solution that will result in non-traumatic in vivo digestion of atherosclerotic plaques. Given the fact that most atherosclerotic plaques are composed of lipids, proteoglycans, collagens, and calcium deposits, it is hypothesized that a “digestion” solution containing agents that specifically target these plaque components will dissolve and digest the plaque in vivo within a clinically relevant time frame, thereby allowing its use alone or in combination with other therapeutic interventions. Ultimately, the optimized digestion solution may be administered via a double balloon occlusion catheter to an isolated segment in the vasculature percutaneously.
This proposed approach to treating severe atherosclerosis percutaneously is innovative, as no therapy exists on the market that is even remotely similar. Devices exist that debulk atherosclerotic plaques, as described above. However, each of these devices induces some form of thermal or mechanical trauma to the arterial wall. The presently disclosed plaque digestion therapy is unique in that it will result in plaque debulking without inducing any trauma to the vascular wall. Thus, this therapy, when successfully developed, has great potential to have a large impact in the clinical arena, given the prevalence of interventions for atherosclerosis.